Restless legs syndrome (RLS) afflicts between 5 and 10% of the general population. Although the clinical origin of RLS is unknown, four characteristic symptoms of RLS exist: 1) lower extremity dysesthesias or paresthesias; 2) motor restlessness; 3) nocturnal increase of paresthesias and motor restlessness; and 4) symptoms that increase at rest, i.e., sitting or lying. Typically, symptoms increase at night (Garcia-Borreguero et al., Neurol. 2002 (11:2) 1573-79). RLS may start at any age, even during childhood, although is usually observed in adults. The clinical course generally changes over time, but tends to become more pronounced with age, with up to 28% of those over 65 being affected (Clark, J. Am. Fam. Prac. 2001 (14:3) 368-374).
RLS is an intensely uncomfortable sensory-motor disorder. Besides sensory symptoms such as paresthesia, which is a sensation of numbness, tingling, burning or pain, accompanied by an urge to move the limbs, patients also experience motor symptoms. When awake and sitting or lying down, the patient may exhibit rhythmic or semi-rhythmic movements of the legs (i.e., dysesthesias). While sleeping, patients frequently demonstrate similar semi-rhythmic legs movements, which have been referred to as periodic leg movements during sleep (PLMS). These jerky leg movements are repetitive, highly stereotypical and are characterized by extension of the big toe along with flexion of the ankle, knee and sometimes the hip (i.e., a Babinski-like movement) (Clark, supra). About 85-90% of RLS sufferers also exhibit PLMS and these patients complain of daytime fatigue and sleepiness or insomnia which have a profound negative effect on quality of life, including daytime fatigue, poor work performance and interrupted social and/or family life (National Institutes of Health, 2003 National Sleep Disorders Research Plan, pp. 76-79).
The origin of RLS and PLMS is unknown and most cases are classified as idiopathic. Clinical and laboratory findings suggest that the dopaminergic neurotransmitter system may be involved. Defects in the opioid and serotonin systems may also play a role (Adler, Clin. Neuropharm. 1997 (20:2) 148-151). RLS is more prevalent in women than men and in individuals of Northern European ancestry. The inheritance pattern of RLS suggests an autosomal dominant mode of transmittance, but the genes accounting for this observation are not known (N.I.H., 2003).
Certain patient populations exhibit RLS more frequently than does the general population. In particular, iron deficiency has been associated with RLS, as have decreased levels of magnesium and folate. Dialysis patients, perhaps because of the prevalence of associated anemia, are frequently afflicted, with 20% to 57% having symptoms of RLS. In addition, pregnant women often complain of RLS, although symptoms usually diminish or disappear after delivery (Clark, supra).
RLS and RLS with PLMS are currently treated with dopaminergic drugs, such as L-dopa, bromocriptine, pergolide, pramipexole or ropinirole. However, dopaminergic drugs have a poor side-effects profile, most notably, causing nausea. In addition, many dopaminergic drugs exhibit a rebound phenomenon, in which symptoms tend to increase as a dose diminishes, such that the patient experiences disruptive problems during the night or early morning. Further, a phenomenon known as augmentation (i.e., patients experience relief of night-time symptoms, but day-time symptoms increase and may spread to other parts of the body, such as the arms) occurs in a majority of patients on long-term dopaminergic therapy. Opiates such as codeine, tramadol, oxycodone and propoxyphene have also been used to treat RLS. The addictiveness of opiates limits use of these narcotics to treat or prevent RLS to severely afflicted patients. Benzodiazepines, particularly clonazepam, are also used to treat mild and sleep-related cases of RLS (Clark, supra). Again, side effects such as daytime drowsiness, confusion and unsteadiness limit the use of benzodiazepines to treat or prevent RLS. In addition, some patients with RLS are refractory to treatment with any current medical therapy.
The γ-aminobutyric acid (γ-aminobutyric acid is abbreviated herein as “GABA”) analog gabapentin (1) has been approved in the United States for the treatment of epileptic seizures and post-herpetic neuralgia. The drug has also shown efficacy in controlled studies for treating neuropathic pain of varying etiologies. Gabapentin has been used to treat a number of other medical disorders (Magnus, Epilepsia 1999, 40, S66-72). In addition, gabapentin has shown utility in treating restless legs syndrome (Mellick et al., Sleep 1996, 19:3, 224-226; Adler, Clin. Neuropharm. 1997, 20:2, 148-151; Ehrenberg et al., Neurol. 1997, 48:3, A278-279; Ehrenberg et al., Neurology 1998, 50:4, A276; Garcia-Borreguero et al., Neurology 2002, 11:2, 1573-79).
The broad pharmaceutical activities of GABA analogs such as gabapentin has
stimulated intensive interest in preparing related compounds that have superior pharmaceutical properties in comparison to GABA, e.g., the ability to cross the blood brain barrier (see, e.g., Satzinger et al., U.S. Pat. No. 4,024,175; Silverman et al, U.S. Pat. No. 5,563,175; Horwell et al., U.S. Pat. No. 6,020,370; Silverman et al., U.S. Pat. No. 6,028,214; Horwell et al., U.S. Pat. No. 6,103,932; Silverman et al., U.S. Pat. No. 6,117,906; Silverman, International Publication No. WO 92/09560; Silverman et al., International Publication No. WO 93/23383; Horwell et al., International Publication No. WO 97/29101, Horwell et al., International Publication No. WO 97/33858; Horwell et al., International Publication No. WO 97/33859; Bryans et al., International Publication No. WO 98/17627; Guglietta et al., International Publication No. WO 99/08671; Bryans et al., International Publication No. WO 99/21824; Bryans et al., International Publication No. WO 99/31057; Belliotti et al., International Publication No. WO 99/31074; Bryans et al., International Publication No. WO 99/31075; Bryans et al., International Publication No. WO 99/61424; Bryans et al., International Publication No. WO 00/15611; Bellioti et al., International Publication No. WO 00/31020; Bryans et al., International Publication No. WO 00/50027; and Bryans et al., International Publication No. WO 02/00209). A number of the above documents disclose the use of gabapentin analogs for the treatment of neuropathic pain states. One analog of particular interest is pregabalin (2), which may possess greater potency in pre-clinical models of pain and epilepsy than gabapentin.
Although the mechanism of action of gabapentin in modulating these aforementioned disease states (including restless leg syndrome) is not understood with certainty, gabapentin, pregabalin and related analogs are known to interact with the α2δ subunit of neuronal voltage-gated calcium channels (Gee et al., J. Biol. Chem. 1996, 271, 5768-5776; Bryans et al., J. Med. Chem. 1998, 41, 1838-1845). A method of administering a compound to a patient which binds an α2δ subunit of a voltage-gated calcium channel has been described. Preferred compounds include the GABA analogs gabapentin and pregabalin (Guttuso, U.S. Pat. No. 6,310,098).
One significant problem associated with the clinical use of many GABA analogs, including gabapentin and pregabalin, is rapid systemic clearance. Consequently, these drugs require frequent dosing to maintain a therapeutic or prophylactic concentration in the systemic circulation (Bryans et al., Med. Res. Rev. 1999, 19, 149-177). For example, dosing regimens of 300-600 mg doses of gabapentin administered three times per day are typically used for anticonvulsive therapy. Higher doses (1800-3600 mg/day in three or four divided doses) are typically used for the treatment of neuropathic pain states.
Although oral sustained released formulations are conventionally used to reduce the dosing frequency of drugs that exhibit rapid systemic clearance, oral sustained release formulations of gabapentin and pregabalin have not been developed because these drugs not absorbed via the large intestine. Rather, these compounds are typically absorbed in the small intestine by one or more amino acid transporters (e.g., the “large neutral amino acid transporter,” see Jezyk et al., Pharm. Res. 1999, 16, 519-526). The limited residence time of both conventional and sustained release oral dosage forms in the proximal absorptive region of the gastrointestinal tract necessitates frequent daily dosing of conventional oral dosage forms of these drugs, and has prevented the successful application of sustained release technologies to many GABA analogs.
One method for overcoming rapid systemic clearance of GABA analogs relies upon the administration of an extended release dosage formulation containing a GABA analog prodrug (Gallop et al., International Publication Nos. WO 02/100347 and WO 02/100349). Such prodrugs may be absorbed over wider regions of the gastrointestinal tract than the parent drug, and across the wall of the colon where sustained release oral dosage forms typically spend a significant portion of gastrointestinal transit time. These prodrugs are typically converted to the parent GABA analog upon absorption in vivo.
Current therapeutic agents for RLS either have significant side effects or are rapidly systemically cleared. Therefore, there is a need in the art for a method of delivering an agent, such as a prodrug of a GABA analog, particularly in extended release dosage forms, with reduced rates of systemic clearance which can also treat or prevent RLS without significant side effects.